Parkinson's disease (PD) is a slow, progressive, debilitative, neurodegenerative disease, which has no cure. The current pharmacological therapies only temporarily mask symptoms, but do not protect neurons from further degeneration. Furthermore, chemotherapeutic agents often cause severe adverse effects and reduce the effectiveness of treatment. Numerous clinical reports have suggested that endurance exercise can slow down disease progression, and add years of independent and quality life to PD patients, or even improve the delivery and efficacy of L-DOPA treatment. Exercise therapy, or in conjunction with drug therapy at early onset of disease state, have been highly advocated by recent clinical trials. The potential health benefit and neurological mechanisms of action for exercise on PD rehabilitation have not been rigorously tested in the laboratory animal models. This research is designed to elucidate the impact of endurance exercise training on nigrostriatal dopamine (DA) neuron plasticity using a slow, progressive, and neurodegenerative mouse model of PD developed and characterized by our laboratory. This model is established based on a regimen of chronic 1-Methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) injections co-administered with probenecid, a drug that inhibits the peripheral and neuronal clearance of MPTP and potentiates the neurotoxicity of MPTP. In this model, we observed a marked decrease of nigrostriatal DA function within one week after treatment and remained low for 6 months. The animal also shows a gradual loss of substantia nigra (SN) neurons, decline of motor activity, and an accumulation of c-synuclein-immunoreactive inclusions in the SN. We further present in the application our preliminary findings supporting the feasibility and potential neuromodulatory role of endurance exercise on enhancing nigrostriatal DA transmission and PD rehabilitation using this model. In this research, we will test the following hypotheses centered on the endurance exercise, when administered at an early stage in the parkinsonian (PK) mice, will 1) improve their mobility and physical rehabilitation, 2) improve the efficacy of L-DOPA, 3) produce these effects by mechanistically causing an elevation of BDNF expression, an increase in the differentiation of DA progenitor cells, and an enhanced DA transmission and plasticity in the nigrostriatal neurons. Findings from this research should provide new insight into the development of alternative therapeutic approaches for enhancing the conventional pharmacological treatment and rehabilitation of PD. Potential benefits for using such a synergistic approach in managing PD would likely reduce the risk of drug toxicity and lower the cost of health care for these patients.